P23 Benchmarking voriconazole therapeutic drug monitoring in adults and paediatrics

Abstract Background Voriconazole is the first-line agent for invasive aspergillosis and microbiology approved fungal infections. Voriconazole acts as both a substrate/inhibitor of several hepatic cytochrome P450 enzymes and demonstrates non-linear kinetics due to metabolism saturation. Inter-individual variability of voriconazole pharmacokinetics is high.1 Therapeutic drug monitoring (TDM) of trough plasma levels can mitigate treatment failure/toxicity. A therapeutic index between 1 and 5.5 mg/L is aimed for.1 An online protocol directs IV/oral dosing in line with British National Formulary guidance. An audit was conducted to benchmark protocol compliance. Standards Total compliance to the following standards was investigated for all voriconazole prescriptions: (i) suitable indication; (ii) documented stop or review date; (iii) protocol prescribed loading and maintenance dose; (iv) dose adjustment for non-therapeutic voriconazole trough level; and (v) trough sampling between 4 and 7 days since initiation. Methods Retrospective voriconazole dispensing data (April 2020–April 2022) was used to identify treated adult and paediatric patients. Correlating electronic prescribing and medicines administration (ePMA) system data was examined in line with standards. Patients receiving voriconazole prophylaxis or under 7 days total treatment were excluded from data collection. Descriptive statistics were used to describe patient characteristics and compliance with standards. Results In total, 47 patients (31 adults and 16 children) were identified. The IQR of age was 48 years. Total compliance was obtained to standard (ii) only. Overall, 94% of patients’ prescriptions possessed an appropriate indication and 6% were clinically appropriate with unclear documented indications. A total of 66% received protocol directed loading and maintenance doses, 6% were prescribed appropriate loading doses, without maintenance doses, and 28% received an inappropriate loading/maintenance dose. Within 4 to 7 days since treatment initiation, 55% had therapeutic trough levels; 27% had supratherapeutic levels, but only 33% of doses were reduced, whereas when subtherapeutic trough levels were encountered in 18% of cases, 75% of doses were increased. Overall, 47% had plasma trough levels taken within the recommended period; 30% did not have a trough level ordered, whilst the remaining 23% had sampling taken before 4 days or after 7 days. Conclusions Person and system interventions are required to improve pre-/post-prescription standards. Prescriber education focusing on indication documentation and recent patient body weight for dosing is required. Whereas an ePMA prescribing package incorporating protocol guidance, consecutive loading and maintenance doses, plus trough sampling orders should be trialled. Protocol integrated instructions on dosing adjustment as done for other TDM drugs should be explored. Occasional nursing omissions of both 12-hourly loading doses on Day 1 of treatment should be addressed with practice educators. Reliance on an external laboratory and third party to communicate trough sample results was associated with delays. This should be investigated further as a cause of dose adjustment issues. ePMA availability of samples, direct laboratory communication with prescribers/pharmacists and investigations into cost-effectiveness of internal laboratory assays should be considered. Interventions should be agreed with stakeholders and reaudit occur. Earlier sampling and dosing practices better representing local the patient population could be investigated further as part of an antimicrobial stewardship improvement project.

Background: Voriconazole is the first-line agent for invasive aspergillosis and microbiology approved fungal infections.Voriconazole acts as both a substrate/inhibitor of several hepatic cytochrome P450 enzymes and demonstrates non-linear kinetics due to metabolism saturation.Inter-individual variability of voriconazole pharmacokinetics is high. 1 Therapeutic drug monitoring (TDM) of trough plasma levels can mitigate treatment failure/toxicity.A therapeutic index between 1 and 5.5 mg/L is aimed for. 1 An online protocol directs IV/oral dosing in line with British National Formulary guidance.An audit was conducted to benchmark protocol compliance.
Standards: Total compliance to the following standards was investigated for all voriconazole prescriptions: (i) suitable indication; (ii) documented stop or review date; (iii) protocol prescribed loading and maintenance dose; (iv) dose adjustment for non-therapeutic voriconazole trough level; and (v) trough sampling between 4 and 7 days since initiation.
Methods: Retrospective voriconazole dispensing data (April 2020-April 2022) was used to identify treated adult and paediatric patients.Correlating electronic prescribing and medicines administration (ePMA) system data was examined in line with standards.Patients receiving voriconazole prophylaxis or under 7 days total treatment were excluded from data collection.Descriptive statistics were used to describe patient characteristics and compliance with standards.
Results: In total, 47 patients (31 adults and 16 children) were identified.The IQR of age was 48 years.Total compliance was obtained to standard (ii) only.Overall, 94% of patients' prescriptions possessed an appropriate indication and 6% were clinically appropriate with unclear documented indications.A total of 66% received protocol directed loading and maintenance doses, 6% were prescribed appropriate loading doses, without maintenance doses, and 28% received an inappropriate loading/ maintenance dose.Within 4 to 7 days since treatment initiation, 55% had therapeutic trough levels; 27% had supratherapeutic levels, but only 33% of doses were reduced, whereas when subtherapeutic trough levels were encountered in 18% of cases, 75% of doses were increased.Overall, 47% had plasma trough levels taken within the recommended period; 30% did not have a trough level ordered, whilst the remaining 23% had sampling taken before 4 days or after 7 days.
Conclusions: Person and system interventions are required to improve pre-/postprescription standards.Prescriber education focusing on indication documentation and recent patient body weight for dosing is required.Whereas an ePMA prescribing package incorporating protocol guidance, consecutive loading and maintenance doses, plus trough sampling orders should be trialled.Protocol integrated instructions on dosing adjustment as done for other TDM drugs should be explored.Occasional nursing omissions of both 12-hourly loading doses on Day 1 of treatment should be addressed with practice educators.Reliance on an external laboratory and third party to communicate trough sample results was associated with delays.This should be investigated further as a cause of dose adjustment issues.ePMA availability of samples, direct laboratory communication with prescribers/pharmacists and investigations into cost-effectiveness of internal laboratory assays should be considered.Interventions should be agreed with stakeholders and reaudit occur.Earlier sampling and dosing practices better representing local the patient population could be investigated further as part of an antimicrobial stewardship improvement project.However, when checked up to 95% are thought to be incorrect with side effects such as nausea, vomiting and gastrointestinal upset often being documented as allergy.Inappropriate and over labelling of penicillin allergy is detrimental to individuals and healthcare systems as alternatives to penicillins are associated with more complications, adverse events, financial costs and extended length of stay.Unnecessary use of penicillin alternatives also increases the risk of antimicrobial resistance development.Penicillin allergy delabelling is a viable option for patients within primary care and acute settings where they meet specific criteria, leading to financial benefits for the health board and optimal treatment outcomes for the patient.NHS Tayside is the first and only Board in Scotland to adopt a whole system approach to de-labelling patients in both acute and community settings.Through the implementation of evidence-based, collaborative and systematic risk assessment processes, clinical teams are able to identify patients who may be eligible for the penicillin allergy de-labelling programme.
If the patient experienced no reaction, they were de-labelled, a request was sent to GP to remove the label and their details were added to a database held by the SLWG.A similar project was piloted in primary care across three Angus GP practices.The aim of the project is to identify a patient population that are labelled penicillin allergic but have received a subsequent prescription for a penicillin allowing a primary care SLWG to carry out a patient consultation with the aim of retrospectively de-labelling and updating the record.This will allow patients to receive optimal treatment options in the future.

Reference1
Patterson T, Thompson GR 3rd, Denning DW et al.Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America.Clin Infect Dis 2016; 63: e1-e60.